There are some aqueous patches which include ketoprofen, which has an anti-inflammatory activity, as an active ingredient (Patent Documents 1 and 2). However, since ketoprofen, being the active ingredient, it has low water-solubility, it is dissolved or dispersed in a paste by using a solubilizer or a dispersant when it is blended in the paste base to make an aqueous patch.
Examples of such solubilizers include particular solubilizers such as crotamiton known as a solubilizer for poorly soluble drugs, fatty acids, fatty acid esters, essential oils, polyalcohols, surfactants, and N-substituted-o-toluidine derivatives (Patent Document 3). On the other hand, in the method using a dispersant, a process including dispersing ketoprofen in a liquid dispersant and mixing it with an acidic adhesive base is used (Patent Document 4).
Such production methods had fundamental drawbacks of low operational efficiency in production, since ketoprofen itself had low water-solubility and therefore the methods required some contrivance.
Specifically, many of such particular solubilizers used for dissolving ketoprofen are generally lipophilic, and careless addition of these solubilizers to other paste components in producing aqueous patches may cause unfavorable effects on the physical properties of the patches such as insolubility of hydrophilic polymers or separation of lipophilic solvents.
Furthermore, in the case of conventional ketoprofen-containing aqueous patches which include glycerin in high concentration as a base component, they had the problem of poor transdermal absorption due to insufficient solubility of ketoprofen in the base. In addition, they also had the problem of poor storage stability, which results from the esterification reaction. In this case, the esterification reaction proceeds between carboxylic acid groups in ketoprofen molecules and hydroxyl groups in polyalcohols (for example, glycerin), lower alcohols, menthol, and the like as solubilizers at even relatively low temperatures by catalysis of weak acids which are base components for aqueous patches, such as organic acids and polyacrylic acid.
Patent Document 5 proposed stabilization of a non-steroidal antiinflammatory analgesic agent which includes ketoprofen having a carboxylic acid group in the molecule by dissolving or dispersing the agent in glycerin and glycol having 3 to 30 carbon atoms. However, there is a concern regarding long-term stability that even the conventional patches described in Patent Document 5 might lose their storage stability due to the esterification reaction, since glycerin is used as a base component when ketoprofen is blended as an active ingredient.
Furthermore, in general, when drugs are dispersed in the patch paste, transdermal absorption of the drugs themselves is reduced while their storage stability is increased. Therefore, there is a demand for a further improved patch which includes ketoprofen as an active ingredient and has both good storage stability and transdermal absorption.
[Patent Document 1] Japanese Patent Laid-Open Sho 58-083623
[Patent Document 2] Japanese Patent Laid-Open Sho 61-275212
[Patent Document 3] International Publication WO 96/11022
[Patent Document 4] Japanese Patent Laid-Open 2006-104170
[Patent Document 5] Japanese Patent Laid-Open 2002-193793